Dapagliflozin Resubmitted to FDA

The FDA has acknowledged receipt of a resubmission of the new drug application (NDA) for dapagliflozin, an SGLT-2 inhibitor for the treatment of type 2 diabetes….

Astra Zeneca and Bristol-Myers Squibb (BMS) have announced that the agency has issued a new Prescription Drug User Fee Act goal date of January 11, 2014, the time by which it needs to make a decision regarding approval, or not, of the product.

Dapagliflozin was rejected by the FDA in January 2012 because of concerns about its risk/benefit profile. At a July 2011 advisory committee meeting to discuss dapagliflozin, the panel had voted 9-6 against recommending approval, primarily as a result of concerns about potential associations with breast and bladder cancer.

However, the product was subsequently approved as Forxigain the European Union earlier this year and is also on the market in Australia, Brazil, Mexico, and New Zealand.

In a statement, Astra Zeneca/BMS said that the NDA resubmission “includes several new studies and additional long-term data (up to four years’ duration) from previously submitted studies, resulting in an overall increase in patient-years exposure to dapagliflozin of more than 50%.”

This comes after the complete response letter issued by the FDA in January 2012 requested “additional data” to allow a better assessment of the benefit/risk profile of dapagliflozin.

If eventually approved in the United States, dapagliflozin will not be the first SGLT-2 inhibitor on the market. Earlier this year, the FDA cleared canagliflozin (Invokana, Janssen Pharmaceuticals) for marketing, and empagliflozin (Boehringer Ingelheim/Lilly) has also recently been filed for approval.

The SGLT-2 inhibitors work by reducing resorption of glucose in the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss.

One of the issues that may hold back their use is the fact that many doctors were trained to think that glucose in the urine is an undesirable thing. SGLT-2 inhibitors thus really target a disease manifestation, rather than a cause of type 2 diabetes, and as such could require a change in mindset necessitating that doctors don’t view this as a step backward.

And although SGLT-2 inhibitors have been associated with some other favorable effects — they lower blood pressure with no increase in heart rate, in addition to reducing triglycerides and increasing high-density lipoprotein cholesterol — they also appear to increase low-density lipoprotein cholesterol, and the significance of this needs to be further investigated. In addition, probably because of the glycosuria they induce, SGLT-2 inhibitors increase the risk for genital mycotic infections and urinary tract infections.

In addition to canagliflozin, dapagliflozin, and empagliflozin, several other SGLT-2 inhibitors are in development, including ipragliflozin (Astellas Pharma) and luseogliflozin (Taisho Pharmaceutical), which are awaiting approval in Japan.